The study of drug metabolism is an important part of the very expensive drug RandD process. In humans and other mammals, many drugs are metabolized through oxidative reactions catalyzed by heme- and cytochrome-containing enzymes. Cytochrome P450 mono-oxygenases, the main enzymes involved in drug oxidative metabolism, have in their active site a heme moiety.
Synthetic metalloporphyrins can serve favorably to mimic oxidative catalytic reactions occurring in biological systems, with the aim of producing and identifying oxidative products of drug candidates, in quantities allowing in vivo studies.
PCT application WO 90/08455 discloses a process for the preparation of oxidative products using various combinations of a synthetic metalloporphyrin, a co-oxidizing reagent, and a solvent. The solvent is generally a CH3CN/CH2Cl2 combination. One of the major inconveniences of processes of this type is the fact that they frequently provide incomplete yields of the sought-after individual products as well as low conversion percentages. As a result, they can rarely be used in a reliable fashion in integrated discovery processes. In fact, their use is generally limited to experimental validation.
In accordance with the present invention, the inventor has unexpectedly found that the yields of oxidative reactions involving metalloporphyrins and which can be useful for the synthesis of metabolites of organic compounds of interest could be increased in a substantial manner through the use of an inert aprotic solvent.
Thus, one of the objects of the present invention is a process for the oxidation of organic compounds. This process comprises reacting the selected organic compound with catalytic amounts of a metalloporphyrin and of an oxidizing agent in the presence of an inert aprotic solvent and recovering the desired products obtained therefrom.
The process of the invention is extremely useful in pharmaceutical research and development as it can be used to perform preliminary evaluations of the metabolic processes which are likely to occur when a given compound is tested in vivo. These preliminary evaluations can be performed rapidly without having to carry out expensive and time consuming in vivo experiments. Furthermore, the process of the present invention provides better yields of individual products than those obtained using prior art processes. In other words, the process of the present invention opens the possibility of obtaining and analyzing in a more systematic fashion a higher number of individual potential metabolites for a given selected compound on which the process is carried out.